Oral squamous cell carcinomas comprise of more than ninety percent of malignancies arising from the oral cavity. Despite recent advances in the past decades, the prognosis in patients remains poor. Better understanding of the complexity of impaired cell growth regulatory elements among these tumors may provide important novel avenues for targeting cancer therapy. The long-term goal of this project is to explore the use of PPAR-gamma signaling pathway as a target for drug therapy in head and neck squamous cell carcinoma. Specifically, the present proposal seeks to establish that activation of FADD-mediated Fas (Fas, CD95, APO-1) apoptosis pathway by peroxisome proliferator-activated receptor-gamma (PPARgamma) signaling underlies an important apoptotic attribute of PPARgamma in oral squamous cell carcinoma. Several signaling pathways, notably phosphatidylinositol 3-kinase and downstream protein kinase B (P13-K/Akt) play a crucial role in evading Fas-mediated tumor cell death. Thus, this hypothesis also seeks to prove that PPARgamma interacts with (P13-K/Akt) signaling pathway to further exert its role in activation of Fas-mediated apoptosis. To test this hypothesis, a molecular approach, including Real-Time PCR, Western Blot, gel shift assays, apoptosis assays, transfection studies, gene knockout, and over-expression vectors will be used to demonstrate the direct role of PPARgamma in mediating tumor cell growth through interaction with Fas and P13-k/Akt pathways.